Two resistance to thyroid hormone mutants with impaired hormone binding

Area of Science:

• Molecular Biology
• Structural Biology
• Endocrinology

Background:

• Resistance to thyroid hormone (RTH) is often caused by mutations in the human thyroid hormone receptor beta (hTRbeta).
• Understanding the structural basis of these mutations is crucial for comprehending RTH pathogenesis.

Purpose of the Study:

• To elucidate the structural mechanisms underlying RTH caused by specific hTRbeta mutations.
• To investigate the impact of Ala 317 Thr and Arg 316 His mutations on ligand binding, transcriptional activity, and receptor dimerization.

Main Methods:

• X-ray crystallography was used to determine the structures of two hTRbeta ligand-binding domain (LBD) mutants: Ala 317 Thr and Arg 316 His.
• Structural analysis focused on the hormone-binding pocket, interactions with ligands, and the role of specific amino acid residues and structural elements like helix 1.

Main Results:

• Both Ala 317 Thr and Arg 316 His mutants exhibited reduced affinity for triiodothyronine (T3) and impaired transcriptional activation.
• The Thr 317 mutation altered the binding of 3,5,3'-triiodothyroacetic acid and affected coregulator interaction surfaces.
• The Arg 316 His mutation disrupted helix 1 stability and abolished TR-TR homodimer formation on DNA.

Conclusions:

• Mutations at positions 317 and 316 in hTRbeta significantly disrupt hormone binding and transcriptional regulation, leading to RTH.
• Helix 1 plays a critical role in linking hormone binding to the overall configuration of the receptor, influencing dimerization and DNA binding.
• The buried polar cluster, involving Arg 316, contributes to helix 1 stability, highlighting its importance in receptor function.